EDITORIAL

Atypical HUS: time to take stock of current guidelinesand outcome measures?

Lesley Rees

Received: 27 December 2012 /Revised: 19 January 2013 /Accepted: 21 January 2013 /Published online: 7 February 2013# IPNA 2013

Abstract European guidelines for the assessment andmanagement of atypical HUS were written in 2009.Since then our understanding of this group of diseaseshas advanced. Evidence is emerging that eculizumab, amonoclonal antibody inhibiting C5 activation, is effec-tive, and potentially superior to current treatment withplasmapheresis. The evidence base for the benefits ofplasmapheresis consists of case series and small reports.Before we embark on a change of management policy itis vital that we set up a system for genetic diagnosis,standardised protocols and a means to collect predeter-mined outcome measures, so that we do not make thesame mistakes with assessment of the effectiveness ofeculizumab as we did for plasmapheresis.

Keywords Hemolytic uremic syndrome .

Thrombocytopenia . Acute kidney injury

Introduction

The term haemolytic uraemic syndrome (HUS) is adescriptive expression for patients presenting with acombination of microangiopathic haemolytic anaemia,thrombocytopaenia and acute kidney injury. It is not,therefore, just as for ‘nephrotic syndrome’ or ‘glomeru-lonephritis’, a diagnosis in itself, but rather a collectionof diseases with differing causes, presentations and out-comes. In addition, it is rare, making clinical trials andstudies of outcome fraught with the difficulties of smallpatient numbers and biases incurred by disease variabil-ity. So how do we decide the best treatment strategies

for patients with atypical HUS (aHUS) and how do weassess outcomes with such diverse aetiologies?

Background

Traditionally, HUS has been divided into diarrhoea-positive(D+) and diarrhoea-negative (D-), the former resulting fromverocytotoxin-producing Escherichia coli and Shigelladysenteriae type 1, the latter encompassing all other causes.In view of the unreliability of diarrhoea as a distin-guishing feature, current terminology used to describeHUS divides it into ‘typical’ for that due to infectivecauses and ‘atypical’ (aHUS) for other causes. TypicalHUS is more common, with verocytotoxin-producingorganisms being the commonest aetiology, although theincidence of Pneumococcal HUS is increasing so that insome countries it is overtaking verocytotoxin-associatedHUS as the commonest cause. aHUS has an incidenceof only two per million population per year, or sevenper million child population, and accounts for approxi-mately 5 % of the total cases of HUS [1]. There areseveral different aetiologies: it may be secondary toautoimmune diseases or occur post transplantation orin association with drugs. However, the most difficultto manage is aHUS that is associated with geneticdisorders of regulation of the alternative pathway ofcomplement. This is because such mutations can causedevastating kidney injury or even death, or can lead toa chronically relapsing course.

The diversity of aHUS due to genetic mutations

To date, genetic mutations can be identified in approximate-ly 50 % of patients with primary aHUS, and more are

L. Rees (*)Great Ormond Street Hospital, London, UKe-mail: I.rees@ucl.ac.uk

Pediatr Nephrol (2013) 28:675–677DOI 10.1007/s00467-013-2423-x

continuously being sought and identified. Some mutationsare more common than others, and prognosis also variesaccording to the mutation. For example, abnormalities ofcomplement Factor H (the most important regulator of thealternative pathway) are the most frequent findings, explain-ing about 30 % of cases, and have the worst prognosis, witha 60–70 % incidence of chronic kidney disease (CKD)within 5 years or death within 1 year, whereas mutationsin membrane cofactor protein (MCP; CD46), which protectscells from damage from complement, have the best out-come, with more than 80 % of patients remaining dialysisindependent, although recurrent episodes are common.Some children can have more than one mutation.Furthermore, most abnormalities are heterozygous, andthere can be incomplete penetrance such that first degreerelatives carrying the same mutation are often asymptomat-ic. Therefore, presumably, for aHUS to develop there mustbe a combination of genetic and environmental factors [2].In other words, the detection of genetic abnormalities pro-vides a risk indicator but is not a good marker alone. Weneed to focus our research on identifying biomarkers forthese diseases and developing metrics for measuring envi-ronment triggers.

Current guidelines for management of aHUS

In 2009, The European Study Group for Atypical HUS pub-lished guidelines for the initial assessment and early manage-ment of children with aHUS [3]. It is stated from the outsetthat this is a consensus document rather than one based onsound evidence. The protocol recommended is plasmaphere-sis within 24 h of diagnosis with whole plasma fractionreplacement fluid [fresh frozen plasma or virus-inactivatedpooled plasma (e.g. Octaplas®)]. Plasmapheresis is then tobe repeated daily for 5 days, followed by five sessions perweek for 2 weeks, then three sessions per week for 2 weeks.There is no further advice for management beyond this point,although most centres would attempt withdrawal of plasma-pheresis if remission has occurred, with variable protocols, butmonitoring for relapse and reinstitution if withdrawal fails.The conclusion to the guidelines is that they should berewritten after 3 years. So, what have we learnt, whatnew developments have there been in the meantime and arewe in a better position now to assess treatment success thanwewere in 2009?

Is plasmapheresis effective?

Dowe knowwhether plasmapheresis is an effective treatment,and who would we expect and who would we not expect tobenefit from it? The underlying rationale of this treatment is to

remove circulating mutated factors or factor H antibodies andto replace deficient ones, such as ADAMTS or complementregulatory factors. Plasmapheresis would not be expected tobenefit patients with MCP deficiency as this is a membrane-bound factor rather than a circulating one. Outcomes haverecently been reviewed [4, 5]. However, most reports stemfrom the days before genetic identification and stratification.Overall, although around 60% of patients with aHUS respondinitially [6], reports suggest that there is a 25 % mortality rateand that 50 % are left with CKD [3]. Furthermore, plasma-pheresis, although a safe procedure with a mortality of lessthan 1 in 10,000 [5], is not without its complications: there arerisks associated with the insertion of vascular access, accessinfection, fluid disturbances during the process itself, hyper-sensitivity reactions, as well as a very small risk of viraltransmission from plasma.

Eculizumab

The most exciting development in the management of aHUSis eculizumab (Soliris®, Alexion Pharmaceuticals, Cheshire,CT), a monoclonal antibody licenced for use in aHUS thattargets C5 and, therefore, the ultimate point in the alternativepathway cascade. There have been small series and casereports of patients who have been successfully treated witheculizmab since the 2009 guidelines were published, alongwith multicentre prospective phase II trials in adults andadolescents and an ongoing paediatric trial. Indeed, there arereported cases of children responding to eculizumab whenplasmapheresis has failed [6]. In this edition of PediatricNephrology, two children are described who had severe neu-rological involvement unresponsive to plasmapheresis, butwho both responded to eculizumab [7]. The drug has beenused for over 10 years in patients with paroxysmal nocturnalhaemoglobinuria and has been demonstrated to have very fewside effects, although the doses used for this disease are about30 % lower than those currently recommended for aHUS [4].All patients need to be vaccinated against Neisseria meningi-tidis before starting treatment, and many physicians use anti-biotic prophylaxis as well. What we do not know iswhen or whether eculizumab can be withdrawn after remis-sion as there are reports of the development of severe relapsein this situation [8]. The European Medicines Agency hasapproved life-long therapy.

Should the guidelines for management of aHUSbe updated?

We are now 3 years further on and it is time to update theEuropean guidelines. At what point do we decide that caseseries or individual reports demonstrating benefit are

676 Pediatr Nephrol (2013) 28:675–677

sufficient to justify following a new treatment plan? Manyclinicians now believe that eculizumab should be the newstandard of care for children with aHUS [2, 3, 6]. Should itbe first line treatment or should it only be used after failureof plasmapheresis? The expense of the drug has to be takeninto consideration, but part of the economics has to includethe social and financial aspects of saving a patient fromdialysis and transplantation. Are we now in a better positionto assess the benefits of eculizumab than we were for assess-ing those of plasmapheresis?

Conclusion

Before we embark on widespread changes of managementpolicy we need to establish that certain criteria are in placeto monitor the effects of our changes. First of all we need tohave a system for rapid genetic screening and diagnosis toenable stratification of outcomes according to mutationanalysis. Secondly, as genetic abnormalities alone are notthe whole answer to disease risk, severity and outcome, weneed to find other biomarkers (such as functional comple-ment pathway assays) and determinants of environmentaltriggers. Thirdly, we must decide upon our definitions forsuccess. Clear outcome measures are death and need forongoing dialysis, but there may be a range of morbidities,such as proteinuria, hypertension, varying grades of CKDand relapses, over an unpredictable time course. Finally, wemust decide what our treatment protocols will be, whetherall children will be treated with the same protocol, and, iftreatment is successful, how long it will be continued for.Should a strategy for treatment withdrawal be part of anyprotocol? Most important of all, the development of regis-tries for aHUS will be critical, but data to determine out-come will only be useful if genetic testing is available and

standardized treatment regimens and outcome definitionsare used to enable useful analysis.

Conflict of interest The author has received educational grants fromAlexion.

References

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